Impact of the vaginal microbiome on topical HIV pre-exposure prophylaxis (PrEP)

阴道微生物组对局部 HIV 暴露前预防 (PrEP) 的影响

• 批准号: 10372984
• 负责人: Betsy C. Herold
• 金额: $ 53.34万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-12 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372984
• 关键词: 15 year old; 16S ribosomal RNA sequencing; AIDS prevention; Active Biological Transport; Address; Adenine; Adherence; Adolescent; Adolescent and Young Adult; Adult; Affect; Age; Anti-Retroviral Agents; Bacteria; Bacterial Vaginosis; Behavioral; Binding; Biologic Characteristic; Biological Assay; Biological Availability; Biological Factors; Biopsy; Black race; Cell Separation; Cells; Centers for Disease Control and Prevention (U.S.); Cervical; Clinical; Clinical Research; Clinical Trials; Complex; Contraceptive Usage; Dapivirine; Data; Development; Diffuse; Dose; Drug Formulations; Drug Kinetics; Drug Transport; Effectiveness; Endocytosis; Epidemic; Equilibrium; Ethnic Origin; Female; Flow Cytometry; Formulation; Frequencies; Gardnerella; Gel; Gene Expression; HIV; HIV risk; Heterosexuals; Human; Immunoglobulin A; Immunoglobulin G; Immunoglobulins; In Vitro; Incubated; Individual; Infection; Inflammation; Inflammatory; Integrase; Integrase Inhibitors; Intervention; Knowledge; Lactobacillus; Latino; Link; Liquid substance; Measures; Metabolic; Metagenomics; Metronidazole; Mucositis; Mucous Membrane; Organic Anion Transporters; Outcome; Participant; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phase; Pilot Projects; Population; Predisposition; Prevention; Prodrugs; Property; Public Health; Race; Risk; Sampling; Seminal fluid; Swab; T-Lymphocyte; Techniques; Technology; Tenofovir; Testing; Time; Tissues; Topical application; Translating; United States; Vagina; Vulnerable Populations; Woman; age group; bacterial community; base; cervicovaginal; cohort; design; drug metabolism; dysbiosis; epidemiology study; fecal microbiome; high risk; men; metabolome; metatranscriptomics; microbial community; microbiome; microbiota; next generation; novel; oral care; phase 1 study; phase III trial; pre-exposure prophylaxis; preclinical development; reproductive tract; response; standard of care; uptake; vaginal microbiome; vaginal microbiota; young woman

Globally, young women represent one of the most vulnerable groups at risk for HIV acquisition highlighting the need for safe, acceptable and effective prevention products. Outcomes in pre-exposure prophylaxis (PrEP) clinical trials have been uniformly disappointing in this high-risk age group, reflecting both behavioral and biological characteristics. The efficacy of PrEP reflects a balance between host susceptibility to HIV and the concentration of drug present in host target cells at the time of exposure. One of the most important biological factors that modulates both the risk of HIV acquisition and the pharmacokinetics and efficacy of topically delivered PrEP products is the vaginal microbiome. Recent studies highlight the complex mechanisms by which individual bacteria and their metabolic products adversely affect the pharmacokinetics of several different PrEP drugs by competing with human cells for drug uptake, inhibiting drug transport into human cells, or metabolizing drugs. Moreover, bacterial vaginosis, which is common in adolescent and young women, is associated with increased HIV risk, possibly reflecting mucosal inflammation. However, the precise mechanisms linking dysbiosis with inflammation and the cumulative effect of the microbiome on PrEP pharmacokinetics are not defined. This application will address this critical knowledge gap and test the overarching hypothesis that vaginal dysbiosis in adolescent and young adult women reduces PrEP efficacy by promoting mucosal inflammation, increasing HIV risk, and decreasing local drug bioavailability. We will use cutting edge technologies including flow cytometry based bacterial cell sorting of immunoglobulin-coated bacteria combined with 16S rRNA sequencing (IgSeq), metagenomic and metatranscriptomic sequencing to evaluate the link between vaginal dysbiosis and mucosal inflammation. Vaginal swabs will be collected from adolescent and young women with symptomatic bacterial vaginosis (BV) before and after standard of care treatment and from asymptomatic controls (no BV) who are frequency matched for age, race/ethnicity and contraceptive use. We will characterize the total bacterial population and the IgA and/or IgG coated and uncoated bacteria and correlate findings with measures of genital tract inflammation including gene expression in vaginal biopsy tissue. We predict that the composition of Ig coated bacteria will differ before and after BV treatment and compared to controls and will identify bacteria that drive genital tract inflammation. Using the clinical samples, we will determine the cumulative effects of bacterial communities and their metabolome on tenofovir-based PrEP (including tenofovir and its prodrugs), assess which mechanisms dominate, and explore potential interventions that might promote more consistent drug pharmacology. We will also evaluate “next-generation” PrEP products including integrase inhibitors. Together, these results will provide rationale for the selection, dosing and formulation of drugs alone or in combination for optimal prevention of HIV in young women.

在全球范围内，年轻女性是最容易感染艾滋病毒的弱势群体之一，这凸显了 需要安全、可接受且有效的暴露前预防 (PrEP) 产品。 在这个高风险年龄组中，临床试验一直令人失望，反映出行为和 PrEP 的功效反映了宿主对 HIV 的易感性与病毒之间的平衡。 暴露时宿主靶细胞中存在的药物浓度是最重要的生物学指标之一。 调节 HIV 感染风险以及局部用药的药代动力学和功效的因素 最近的研究强调了阴道微生物群的复杂机制。 个别细菌及其代谢产物对几种不同 PrEP 的药代动力学产生不利影响 人体细胞竞争药物摄取、抑制药物转运至人体细胞或代谢 此外，在青少年和年轻女性中常见的细菌性阴道病与 HIV风险增加，可能反映了粘膜炎症，然而，与菌群失调相关的确切机制。 炎症和微生物组对 PrEP 药代动力学的累积影响尚未确定。 应用程序将解决这一关键的知识差距，并测试阴道菌群失调的总体假设 青少年和年轻成年女性通过促进粘膜炎症、增加 HIV 感染来降低 PrEP 的功效 我们将使用包括流式细胞术在内的尖端技术。 基于免疫球蛋白包被细菌的细菌细胞分选结合 16S rRNA 测序 (IgSeq)， 宏基因组和宏转录组测序评估阴道菌群失调与粘膜之间的联系 将从有症状细菌的青少年和年轻女性身上采集阴道拭子。 标准护理治疗前后的阴道病 (BV) 以及无症状对照 (无 BV) 的患者 与年龄、种族/民族和避孕措施相匹配的频率我们将描述细菌总数的特征。 群体和 IgA 和/或 IgG 包被和未包被的细菌，并将结果与​​生殖器测量相关联 阴道活检组织中的炎症包括基因表达，我们预测Ig的组成。 包被细菌在 BV 处理前后以及与对照相比会有所不同，并且会识别出以下细菌： 使用临床样本，我们将确定细菌的累积效应。 基于替诺福韦的 PrEP（包括替诺福韦及其前药）的社区及其代谢组，评估哪些 机制占主导地位，并探索可能促进更一致药物的潜在干预措施 我们还将一起评估“下一代”PrEP 产品，包括整合酶抑制剂。 这些结果将为单独或联合用药的选择、剂量和配制提供依据。 年轻女性艾滋病毒的最佳预防。